In the United States this year, almost 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) will be diagnosed, and approximately 11,000 deaths will result from this disease. Alcohol use and tobacco smoking act synergistically in causing this disease, although exposure to the human papilloma virus (HPV) is now also linked to HNSCC risk. In addition to risks related to exposures and lifestyle factors, susceptibility for HNSCC has been linked to polymorphic variation in key genes important to a number of cellular processes related to carcinogenesis. However, overall, the mechanism responsible for induction of the cellular changes that give rise to HNSCC remains incompletely understood and novel approaches are needed to further advance our knowledge. In the post-genomic era, epigenetic regulation has emerged as critical mode by which the expression of genes can be controlled. DNA CpG island methylation, a specific and well studied epigenetic mark, can lead to inactivation of a gene in a heritable and stable fashion. Recent work has suggested that there are systematic differences in the carcinogenic exposures that induce distinct classes of alterations in cancer cells. The current proposal is based upon a new paradigm stating that variation in exposure is associated with predictable differences in somatic alteration to the cancer cell epigenome. We believe that investigating this paradigm may yield powerful markers of susceptibility for human cancer. Specifically, we hypothesize that there are distinct subgroups of HNSCCs characterized by a predominant phenotype that can be broadly grouped as displaying genetic alterations or epigenetic alterations. Further, our data suggest that environmental, lifestyle and viral (HPV) factors significantly drive these phenotypes. We will apply molecular epidemiologic methods to examine this hypothesis, utilizing the resources of an existing, population-based case control study of HNSCC. The aims of this project are to study all of the cancers collected from volunteers in the parent study and to identify subgroups of tumors where (1) somatic genetic deletion events predominate or (2) somatic DNA methylation silencing (epigenetic events) predominates. We will examine how differences in methylation and deletion of critical DNA regions associate with smoking exposure, alcohol use and dietary deficiencies in driving oral carcinogenesis. We will further use a pathway approach to ask if there are normal genetic polymorphisms that interact with these somatic events, predisposing individuals to susceptibility to either particular type of cancer associated somatic change. All of this will be completed using validated, high- throughput methodologies. Using this novel approach, this data will aid in identifying the carcinogenic mechanisms associated with susceptibility to the carcinogenic activities of alcohol, smoking, and dietary deficiencies. PUBLIC HEALTH RELEVANCE: This project "Patterns of Somatic Gene Alterations in Oral Cancer" will investigate the relationship of the major risk factors for Head and Neck cancers with the pattern of inactivation of the major genes responsible for causing these tumors. We believe that the underlying patterns of gene changes may predict disease outcome and lead to new understanding of this cancer, enhancing our ability to both prevent and treat the disease.